I. Candidate I am a board-certified orthodontist and a research-track faculty at the UCLA School of Dentistry. I am a dual- trained clinician scientist, with significant background in bone tissue engineering with 16 publications, 24 podium abstract presentations, and 6 national-level excellence-in-research awards to date. For the past 7 years I have worked extensively with various transdisciplinary research teams at UCLA, based on which I have sought primary mentorship from Dr. Chia Soo and formed the five-person advisory committee of the current proposal. Under Dr. Soo's new mentorship, I am in the path of establishing a clear independence from my previous and current mentors' work, evidenced by my recent achievements delineated in the current proposal. My immediate career goals are to secure time and effort for research career development by means of a K08 award, continue devising innovations relevant to the Nation's research needs, and build upon my prolific publication record. My end goal is for scientific independence in a tenure faculty position, and to continue addressing the Nation's biomedical and clinical research needs by transdisciplinary efforts. A K08 award will tremendously benefit my career development by providing (i) a structured program to cultivate multidisciplinary research skills, (ii) salary support to maintain commitment to research-track, and (iii) protected research time. The astonishing five-member advisory committee assembled for this proposal consists of developmental and molecular biologists, clinician scientists with FDA experience, and bioengineer to provide mentorship in this highly translational and multidisciplinary project. The distinguished and experienced mentors are composed of leading members of the UCLA research community, and will provide both research and administrative support. In addition to receiving unanimous institutional backing from the School of Dentistry, I will benefit from and strengthen the robust collaboration that exists between my mentors and their research collaborators. II. Environment UCLA is one of the leading public research institutions in the world and provides an excellent academic environment with rich intellectual resources, abundant research facilities, and robust institutional support. The institutional environment at UCLA offers a great wealth of closely integrated and shared physical and human resources that can foster the growth and intellectual development of a young scientific investigator. III. Research Dental osteopenia and its associated morbidities such as tooth loss, periodontal implant failures, and malfitting dentures are projected to cost over $240 billion worldwide by 2040. Therapeutic approaches to osteoporotic bone loss have focused on either anabolic or antiresorptive agents. However, there is a pressing need to develop new agents that target both bone formation and resorption. Importantly, there is no concrete evidence that supports whether an osteoporosis therapy can also prevent the dentoalveolar osteopenia frequently seen in post-menopausal osteoporotic patients. NELL-1 is a potent pro-osteogenic and anti-resorptive protein that was recently found to exert a systemic, protective function against osteoporotic bone loss. PEGylation of NELL-1 (NELL-PEG) has enhanced NELL-1's pharmacokinetics as a systemic therapy. As a result, preliminary studies demonstrate that systemic NELL-PEG regenerates ovariectomy-induced bone loss not only in long bones, but also in maxillary alveolar bone in mice. This has led to our central hypothesis that systemic NELL-PEG therapy can reverse osteoporotic bone loss in both postcranial (appendicular and axial) and craniofacial (cranium, maxilla, and mandible) skeleton. We will test this hypothesis in three specific aims: AIM 1. Determine the pharmacokinetics and the targeting efficiency of NELL-1 and PEGylated NELL-1. In this aim, we will determine the pharmacokinetic profile of systemic NELL-PEG in bone and plasma over an 8-week period. Both postcranial and craniofacial bones will be analyzed. AIM 2. Determine the therapeutic efficacy of PEGylated NELL-1 in regenerating jaw bones alongside postcranial bones in osteoporotic mice. AIM 2A will evaluate the effect of systemic NELL-PEG on craniofacial versus postcranial bones in OVX-induced osteoporotic mice. Previously determined formulations of systemic NELL-PEG will be tested, and bone density, formation, and turnover will be assessed. Concurrently, AIM 2B will evaluate systemic NELL-PEG effects on the number and activity of stem cells, osteoblasts (OB), and osteoclasts (OC) in the mandible, long bone and vertebra. AIM 3. Examine the effects of Nell-1 on craniofacial versus postcranial skeletal development and maintenance in osteoblast-specific transgenic knockout mice. In this aim, we will cross our recently generated Nell-1flox/flox mice with 2.3kb Col1-Cre and Wnt1-Cre to examine osteoblast and neural crest specific effects, respectively. Novel rNELL-1 based therapies can vastly improve the standard of care for the treatment of osteoporosis, dental osteopenia and its morbidities. Development of a systemic therapy that can promote dual anabolic and anti-osteoclastic effects in craniofacial and postcranial bones alike would provide a groundbreaking therapy.